This invention relates to novel sulfonamide substituted diphenyl urea compounds, pharmaceutical compositions, processes for their preparation, and use thereof in treating IL-8, GROxcex1, GROxcex2, GROxcex3, NAP-2 and ENA-78 mediated diseases.
Many different names have been applied to Interleukin-8 (IL-8), such as neutrophil attractant/activation protein-1 (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor. Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells. It is produced by a majority of nucleated cells including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, IL-1xcex1, IL-1xcex2or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP. M. Baggiolini et al., J. Clin. Invest. 84, 1045 (1989): J. Schroder et al, J. Immunol. 139, 3474 (1987) and J. Immunol. 144, 2223 (1990); Strieter, et al., Science 243, 1467 (1989) and J. Biol. Chem. 264, 10621 (1989); Cassatella et al., J. Immunol. 148, 3216 (1992).
GROxcex1, GROxcex2, GROxcex3and NAP-2 also belong to the chemokine family. Like IL-8 these chemokines have also been referred to by different names. For instance GROxcex1, xcex2, xcex3 have been referred to as MGSAxcex1, xcex2 and xcex3 respectively (Melanoma Growth Stimulating Activity), see Richmond et al., J. Cell Physiology 129, 375 (1986) and Chang et al., J. Immunol 148, 451 (1992). All of the chemokines of the xcex1-family which possess the ELR motif directly preceding the CXC motif bind to the IL-8 B receptor (CXCR2). IL-8, GROxcex1, GROxcex2, GROxcex3, NAP-2, and ENA-78 stimulate a number of functions in vitro. They have all been shown to have chemoattractant properties for neutrophils, while IL-8 and GROxcex1 have demonstrated T-lymphocytes, and basophilic chemotactic activity. In addition IL-8 can induce histamine release from basophils from both normal and atopic individuals. GRO-xcex1 and IL-8 can in addition, induce lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CD11b/CD18) on neutrophils without de novo protein synthesis. This may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many known diseases are characterized by massive neutrophil infiltration. As IL-8, GROxcex1, GROxcex2, GROxcex3and NAP-2 promote the accumulation and activation of neutrophils, these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis, Baggiolini et al., FEBS Lett. 307, 97 (1992); Miller et al., Crit. Rev. Immunol. 12, 17 (1992); Oppenheim et al., Annu. Rev. Immunol. 9, 617 (1991); Seitz et al., J. Clin. Invest. 87, 463 (1991); Miller et al., Am. Rev. Respir. Dis. 146, 427 (1992); Donnely et al., Lancet 341, 643 (1993). In addition the ELR chemokines (those containing the amino acids ELR motif just prior to the CXC motif) have also been implicated in angiostasis, Strieter et al., Science 258, 1798 (1992).
In vitro, IL-8, GROxcex1, GROxcex2, GROxcex3 and NAP-2 induce neutrophil shape change, chemotaxis, granule release, and respiratory burst, by binding to and activating receptors of the seven-transmembrane, G-protein-linked family, in particular by binding to IL-8 receptors, most notably the IL-85xcex2receptor (CXCR2). Thomas et al., J. Biol. Chem. 266, 14839 (1991); and Holmes et al., Science 253, 1278 (1991). The development of non-peptide small molecule antagonists for members of this receptor family has precedent. For a review see R. Freidinger in: Progress in Drug Research, Vol. 40, pp. 33-98, Birkhauser Verlag, Basel 1993. Hence, the IL-8 receptor represents a promising target for the development of novel anti-inflammatory agents.
Two high affinity human IL-8 receptors (77% homology) have been characterized: IL-8Rxcex1, which binds only IL-8 with high affinity, and IL-8Rxcex2, which has high affinity for IL-8 as well as for GROxcex1, GROxcex2, GROxcex3 and NAP-2. See Holmes et al., supra; Murphy et al., Science 253, 1280 (1991); Lee et al., J. Biol. Chem. 267, 16283 (1992); LaRosa et al., J. Biol. Chem. 267, 25402 (1992); and Gayle et al., J. Biol. Chem. 268, 7283 (1993).
There remains a need for treatment, in this field, for compounds, which are capable of binding to the IL-8xcex1 or xcex2 receptor. Therefore, conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophil and T-cells subsets into the inflammatory site) would benefit by compounds, which are inhibitors of IL-8 receptor binding.
This invention provides for a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8a or b receptor and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In particular the chemokine is IL-8.
This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I).
The present invention also provides for the novel compounds of Formula (I), and pharmaceutical compositions comprising a compound of Formula (I), and a pharmaceutical carrier or diluent.
Compounds of Formula (I) useful in the present invention are represented by the structure: 
wherein
Rb is independently hydrogen, NR6R7, OH, ORa, C1-5alkyl, aryl, arylC1-4alkyl, aryl C2-4alkenyl; cycloalkyl, cycloalkyl C1-5alkyl, heteroaryl, heteroarylC1-4alkyl, heteroarylC2-4alkenyl, heterocyclic, heterocyclic C1-4alkyl, or a heterocyclic C2-4alkenyl moiety, all of which moieties may be optionally substituted one to three times independently by halogen; nitro; halosubstituted C1-4alkyl; C1-4 alkyl; amino, mono or di-C1-4alkyl substituted amine; ORa; C(O)Ra; NRaC(O)ORa; OC(O)NR6R7; hydroxy; NR9C(O)Ra; S(O)m, Ra; C(O)NR6R7; C(O)OH; C(O)ORa; S(O)tNR6R7; NHS(O)tRa. Alternatively, the two Rb substituents can join to form a 3-10 membered ring, optionally substituted and containing, in addition to optionally substituted C1-4alkyl, independently, 1 to 3 NRa, O, S, SO, or S2 moities which can be optionally unsaturated;
Rais an alkyl, aryl, arylC1-4alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic, COORaxe2x80x2, or a heterocyclic C1-4alkyl moiety, all of which moieties may be optionally substituted;
Raxe2x80x2 is an alkyl, aryl, arylC1-4alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic or a heterocyclic C1-4alkyl moiety, all of which moieties may be optionally substituted;
m is an integer having a value of 1 to 3;
mxe2x80x2 is 0, or an integer having a value of 1 or 2;
n is an integer having a value of 1 to 3;
q is 0, or an integer having a value of 1 to 10;
t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;
R1 is independently selected from hydrogen, halogen, nitro, cyano, C1-10 alkyl, halosubstituted C1-10alkyl, C2-10alkenyl, C1-10alkoxy, halosubstituted C1-10alkoxy, azide, S(O)tR4, (CR8R8)q S(O)tR4, hydroxy, hydroxy substituted C1-4alkyl, aryl, aryl C1-4alkyl, aryl C2-10alkenyl, aryloxy, aryl C1-4 alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl C2-10 alkenyl, heteroaryl C1-4 alkyloxy, heterocyclic, heterocyclic C1-4alkyl, heterocyclicC1-4alkyloxy, heterocyclicC2-10 alkenyl, (CR8R8)q NR4R5, (CR8R8)qC(O)NR4R5, C2-10 alkenyl C(O)NR4R5, (CR8R8)q C(O)NR4R10, S(O)3R8, (CR8R8)q C(O)R11, C2-10 alkenyl C(O)R11, C2-10alkenyl C(O)OR11, (CR8R8)q C(O)OR11, (CR8R8)q OC(O)R11, (CR8R8)qNR4C(O)R11, (CR8R8)q C(NR4)NR4R5, (CR8R8)q NR4C(NR5)R11, (CR8R8)q NHS(O)tR13, (CR8R8)q S(O)tNR4R5, or two R1 moieties together may form Oxe2x80x94(CH2)sO or a 5 to 6 membered saturated or unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moieties may be optionally substituted;
R4 and R5 are independently hydrogen, optionally substituted C1-4alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, heterocyclic, heterocyclicC1-4alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O, N and S;
R6 and R7 are independently hydrogen, or a C1-4 alkyl, heteroaryl, aryl, aklyl aryl, alkyl C1-4heteroalkyl, which may all be optionally substituted or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom is selected from oxygen, nitrogen or sulfur, and which ring may be optionally substituted;
Y is hydrogen, halogen, nitro, cyano, halosubstituted C1-10 alkyl, C1-10 alkyl, C2-10 alkenyl, C1-10 alkoxy, halosubstituted C1-10 alkoxy, azide, (CR8R8)qS(O)tRa, (CR8R8)ORa, hydroxy, hydroxy substituted C1-4alkyl, aryl; aryl C1-4 alkyl, aryloxy, arylC1-4alkyloxy, arylC2-10 alkenyl, heteroaryl, heteroarylalkyl, heteroaryl C1-4 alkyloxy, heteroaryl C2-10 alkenyl, heterocyclic, heterocyclic C1-4alkyl, heterocyclicC2-10 alkenyl, (CR8R8)qNR4R5, C2-10 alkenyl C(O)NR4R5, (CR8R8)qC(O)NR4R5, (CR8R8)q C(O)NR4R10, S(O )3R8, (CR8R8)qC(O)R11, C2-10alkenylC(O)R11, (CR8R8)qC(O)OR11, C2-10alkenylC(O)OR11, (CR8R8)qOC(O)R11, (CR8R8)qNR4C(O)R11, (CR8R8)q NHS(O)tR13, (CR8R8)q S(O)tNR4R5, (CR8R8)qC(NR4)NR4R5, (CR8R8)q NR4C(NR5)R11, or two Y moieties together may form Oxe2x80x94(CH2)sxe2x80x94O or a 5 to 6 membered saturated or unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted;
R8 is hydrogen or C1-4 alkyl;
R9 is hydrogen or a C1-4alkyl;
R10 is C1-10 alkyl C(O )2R8; 
R11 is hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC1-4alkyl;
R13 is suitably C1-4 alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclicC1-4alkyl; or a pharmaceutically acceptable salt thereof.